Engineering a pharmacologically superior form of leptin for the treatment of obesity

Leptin plays a central role in the homeostasis of body weight through its regulatory effects on appetite and energy expenditure, yet in trials as a therapeutic agent for the treatment of obesity in humans it has been disappointing. The poor clinical efficacy of leptin results from its short circulating half-life, low potency and poor solubility, necessitating large and frequent doses to obtain even modest clinical benefit. Engineered Fc-leptin immunofusins, consisting of the Fc fragment of an immunoglobulin gamma chain followed by leptin, exhibit improved pharmacological properties with very consistent and potent biological activities. Furthermore, in extending the circulating half-life of the protein in vivo from a few minutes for leptin to many hours for Fc-leptin, these proteins have the potential to reduce drastically the dosage and frequency of administration required to obtain clinical benefit. The results of this study show that the engineered leptin immunofusins described here have significantly enhanced pharmacological properties in comparison with the recombinant leptin that was used in clinical trials. As such, they could represent an important step towards a therapeutically superior form of leptin if the disappointing performance of leptin in early clinical trials was due to its poor pharmacological properties rather than any conceptual weakness in the strategy of using leptin for the treatment of obesity and its related disorders.     

Study of the Transit-Time Limitations of the Impulse Response in Mid-Wave Infrared HgCdTe Avalanche Photodiodes

The impulse response in frontside-illuminated mid-wave infrared HgCdTe electron avalanche photodiodes (APDs) has been measured with localized photoexcitation at varying positions in the depletion layer. Gain measurements have shown an exponential gain, with a maximum value of M = 5000 for the diffusion current at a reverse bias of V _b = 12 V. When the light was injected in the depletion layer, the gain was reduced as the injection approached the N+ edge of the junction. The impulse response was limited by the diode series resistance–capacitance product, RC, due to the large capacitance of the diode metallization. Hence, the fall time is given by the RC constant, estimated as RC = 270 ps, and the rise time is due to the charging of the diode capacitance via the transit and multiplication of carriers in the depletion layer. The latter varies between t _10–90 = 20 ps (at intermediate gains M < 500) and t _10–90 = 70 ps (at M = 3500). The corresponding RC-limited bandwidth is BW = 600 MHz, which yields a new absolute record in gain–bandwidth product of GBW = 2.1 THz. The increase in rise time at high gains indicates the existence of a limit in the transit-time-limited gain–bandwidth product, GBW = 19 THz. The impulse response was modeled using a one-dimensional deterministic model, which allowed a quantitative analysis of the data in terms of the average velocity of electrons and holes. The fitting of the data yielded a saturation of the electron and hole velocity of v _e = 2.3 × 10⁷ cm/s and v _h = 1.0 × 10⁷ cm/s at electric fields E > 1.5 kV/cm. The increase in rise time at high bias is consistent with the results of Monte Carlo simulations and can be partly explained by a reduction of the electron saturation velocity due to frequent impact ionization. Finally, the model was used to predict the bandwidth in diodes with shorter RC = 5 ps, giving BW = 16 GHz and BW = 21 GHz for x _j = 4 μm and x _j = 2 μm, respectively, for a gain of M = 100.     

Exposure levels to brominated compounds in seawater swimming pools treated with chlorine

Despite evidence of formation of brominated compounds in seawater swimming pools treated with chlorine, no data about exposure levels to these compounds have been reported. To address this issue, a survey has been carried out in four establishments (representing 8 pools) fed with seawater and devoted to relaxing and cure treatments (thalassotherapy centres located in Southeast of France). Carcinogenic and mutagenic brominated disinfection byproducts (trihalomethanes -THM- and halogenated acetic acids -HAA-) were quantified at varying levels, statistically related to organic loadings brought by bathers, and not from marine organic matter, and also linked to activities carried out in the pools (watergym vs swimming). Bromoform and dibromoacetic acid, the most abundant THM and HAA detected, were measured at levels up to 18-fold greater than the maximum contaminant levels of 60 and 80 μg/L fixed by US.EPA in drinking waters. The correlations between these disinfection byproducts and other environmental factors such as nitrogen, pH, temperature, free residual chlorine, UV₂₅₄, chloride and bromide concentrations, and daily frequentation were examined. Because thalassotherapy and seawater swimming pools (hotels, cruise ships,…) are increasing in use around the world and because carcinogenic and mutagenic brominated byproducts may be produced in chlorinated seawater swimming pools, specific care should be taken to assure cleanliness of users (swimmers and patients taking the waters) and to increase water circulation through media filters to reduce levels of brominated byproducts.     

Predicting suspended sediment concentration from nephelometric turbidity in organic‐rich waters

Nephelometric turbidity is an optical index for the side scattering of light caused by fine particles suspended in water. When a mixed composition of suspended inorganic and organic materials, including dissolved organic material, is present, turbidity measurements can be affected by the different optical properties of the organic and inorganic materials present, and different turbidimeters are more or less sensitive to these influences. Two different methods of nephelometric turbidity measurement were assessed (using instruments confirming to two different turbidity standard methods: EPA 180.1 and ISO 7027). We investigated the influence of particulate organic matter and coloured dissolved organic matter on relationships between turbidity and suspended sediment concentration for rivers in diverse Otago catchments, in the South Island of New Zealand. The presence of organic matter and dissolved colour affected turbidity measurement owing to light absorption; however, turbidity measurement following the ISO 7027 standard, which specifies near infrared radiation at wavelengths where organic absorption is very weak, was less affected by organics. As a result, rating equations between suspended sediment and turbidity may be significantly different with ISO 7027 compared with EPA 180.1 methods.     

Aspects of stadium design for warm climates

The airflow pattern on the spectators' terrace in stadia is affected by numerous architectural factors, such as form, size, permeability, i.e. the morphology of the building. A stadium design not taking into account the prevailing environmental parameters can result in unpleasant thermal and aerodynamic environment in the stadium bowl.     

Comparison of PCR and quantitative real-time PCR methods for the characterization of ruminant and cattle fecal pollution sources

The State of California has mandated the preparation of a guidance document on the application of fecal source identification methods for recreational water quality management. California contains the fifth highest population of cattle in the United States, making the inclusion of cow-associated methods a logical choice. Because the performance of these methods has been shown to change based on geography and/or local animal feeding practices, laboratory comparisons are needed to determine which assays are best suited for implementation. We describe the performance characterization of two end-point PCR assays (CF128 and CF193) and five real-time quantitative PCR (qPCR) assays (Rum2Bac, BacR, BacCow, CowM2, and CowM3) reported to be associated with either ruminant or cattle feces. Each assay was tested against a blinded set of 38 reference challenge filters (19 duplicate samples) containing fecal pollution from 12 different sources suspected to impact water quality. The abundance of each host-associated genetic marker was measured for qPCR-based assays in both target and non-target animals and compared to quantities of total DNA mass, wet mass of fecal material, as well as Bacteroidales, and enterococci determined by 16S rRNA qPCR and culture-based approaches (enterococci only). Ruminant- and cow-associated genetic markers were detected in all filters containing a cattle fecal source. However, some assays cross-reacted with non-target pollution sources. A large amount of variability was evident across laboratories when protocols were not fixed suggesting that protocol standardization will be necessary for widespread implementation. Finally, performance metrics indicate that the cattle-associated CowM2 qPCR method combined with either the BacR or Rum2Bac ruminant-associated methods are most suitable for implementation.     

Drying nano particles solution on an oscillating tip at an air liquid interface: what we can learn, what we can do

Evaporation of fluid at micro and nanometer scale may be used to self-assemble nanometre-sized particles in suspension. Evaporating process can be used to gently control flow in micro and nanofluidics, thus providing a potential mean to design a fine pattern onto a surface or to functionalize a nanoprobe tip. In this paper, we present an original experimental approach to explore this open and rather virgin domain. We use an oscillating tip at an air liquid interface with a controlled dipping depth of the tip within the range of the micrometer. Also, very small dipping depths of a few ten nanometers were achieved with multi walls carbon nanotubes glued at the tip apex. The liquid is an aqueous solution of functionalized nanoparticles diluted in water. Evaporation of water is the driving force determining the arrangement of nanoparticles on the tip. The results show various nanoparticles deposition patterns, from which the deposits can be classified in two categories. The type of deposit is shown to be strongly dependent on whether or not the triple line is pinned and of the peptide coating of the gold nanoparticle. In order to assess the classification, companion dynamical studies of nanomeniscus and related dissipation processes involved with thinning effects are presented.